2,3,6,7-tetrahydro-6-phenyl-5h-imidazo(1,2-d)+8 1,4)benzodiazepin-5-ones and diazepines

ABSTRACT

IN WHICH   Compounds of the formula: D R A W I N G R is -H or -Cl; R1 is -H or -CH3; and PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF POSSESS CENTRAL NERVOUS SYSTEM ACTIVITY AND ADDITIONALLY, THE 1,4BENZODIAZEPINE FORM OF THE COMPOUNDS EXHIBIT ANTAGONISM OF RESERPINE INDUCED PTOSIS OF THE EYELID IN STANDARD EXPERIMENTAL ANIMALS.

United States Patent [191 Buzby, Jr. et al.

[ Nov. 18, 1975 2,3,6,7-TETRAHYDRO-6-PHENYL-5H- IMIDAZO[ 1,2-D] 1 ,4lBENZODIAZEPIN- S-ONES AND DIAZEPINES [75] Inventors: George C. Buzby,Jr., Philadelphia; Harshavedan C. Shah, Secane, both of Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: Sept. 9, 1974 [21] App]. No.: 504,408

52 US. Cl 260/309.6;424/273 51 Int. c13 c071) 49/34 58 Field of Search260/309.6

[56] References Cited UNITED STATES PATENTS 8/1970 Derieg et al.260/309.6

OTHER PUBLICATIONS Chem. Abstracts, 73:25542y.

Primary ExaminerEthel G. Love Attorney, Agent, or FirmRichard K. Jackson[57] 7 ABSTRACT Compounds of the formula:

N 1 l IZR \X in which X is CH, or C- 8 Claims, No Drawings2,3,6,7-TETRAHYDRO-6-PHENYL-5H- lMIDAZO[1,2-D][1 ,4 ]BENZODIAZEPIN -ONESAND DIAZEPINES DESCRIPTION OF THE INVENTION In accordance with thisinvention there is provided a group of central nervous systemdepressants useful in inducing a sedative response in warm-bloodedanimals, which depressants present the structural formula:

HCl/

in which R is H or CH;; and pharmaceutically acceptable thereof.

The compounds of this invention are prepared by condensing an imidazoaniline with an alpha halophenylacetic acid halide followed by ringclosure under basic conditions and chemical reduction of the resultingketone. The imidazo aniline starting materials are produced bycondensing methyl anthranilate or an appropriately ring substitutedderivative thereof, with an aromatic sulfonylchloride such as p-methoxybenzene sulfonyl chloride followed by reaction with 1,2-diamino-Z-methyl propane or l,2-diamino ethane to obtain thecorresponding 2-imidazolin-2-yl-N-(4- methoxybenzenesulfonyl)anilinederivatives which are desulfonylated to afford the 2-imidazol-2-ylaniline precursors. The preparation of the imidazo aniline precursors isexemplified as follows:

Dissolve grams of methyl anthranilate in pyridine (l5 milliliters) andbenzene (100 milliliters) and add a stoichiometric amount ofp-methoxybenzenesulfonyl chloride. After standing for 4 hours theprecipitate is removed by filtration, washed with benzene and thefiltrate evaporated to dryness. Recrystallization of the residue gavemethyl o-(4-aminobenzenesulfonamido) benzoate (25.0 grams,'melting range8l-85C.). Reflux the product (5.0 grams) overnight with 1,2-diamino-Z-methyl propane (50 milliliters). Remove the excess diamineunder vacuum and heat the residue at l70l90C. on an oil bath strippingat 0.5 millimeters Hg vacuum. The solidified contents of the flask isrecrystallized from ethanol-benzene to provide 2'[4,4(or5,5)dimethyl-2-imidazolin-2-yl]-4-methoxy benzene sulfonanilide (5.475grams, melting range 202205C.) which is desulfonylated by heating on asteam bath overnight with 92 percent H 80 (102 milliacid addition saltsliters concentrated H 80 plus 12 milliliters H O) followed by coolingand pouring the product into ice water containing excess NH OH. Extractwith methylene chloride, dry and remove the solvent to obtain 0- [4,4(or 5,5 )dimethyl-2-imidazolin-2-yl]aniline. The corresponding imidazoaniline precursor devoid of gem-dimethyl groups is made in the same wayby employing 1,2-diamino ethane as the reactant. Likewise, benzenesulfonyl chlorides in general may be employed in lieu of thep-methoxybenzene sulfonyl chloride specifically employed herein.

The imidazo aniline precursors condense with the alpha halophenylacetylhalides CH XCOX smoothly in an inert organic solvent or diluent such asmethylene chloride, to provide an open amide of the formula:

which undergo chemical reduction with reagents such as LiAll-l,

to afford the benzodiazepine structure.

R being H, halogen, alkyl, alkoxy, CF NO NH and the like.

The compounds of this invention are central nervous system depressants.They present an activity profile consistent with a sedative ortranquilizer in the standard experimental animal. The compounds areuseful in eliciting a calming effect in warm blooded animals. Inaddition to their central nervous system depressant activity, the1,4-benzodiazepines of this invention produce antagonism towardreserpine induced ptosis in the mouse. Based upon that activity. andtheir sedating properties, the 1,4-benzodiazepines of this invention arecatagorized as possessing both central nervous system depressantactivity and thymoleptic activity and are useful as sedatives and moodelevators.

The central nervous system depressantactivityof the compounds of thisinvention was determined in vivo by administering each of the compoundsorally to three mice weighing from 14 to 24 grams at each of the dosagelevels 400, 127, 40, 12.7, 4.0 and 1.27 milligrams per kilogram bodyweight. The mice were observed for at least 2 hours to determine theeffect of the compound. With the compounds of this invention, theobservations included some signs of stimulation including twitches,tremors and mild convulsions at doses exceeding 127 mg/kg body weight,marked depression at doses generally from 0.400 to 40 mg/kg withautonomic activity evidenced by ptosis at 400 mg/kg and mydriasis at0.400 mg/kg (suggesting anti-cholinergic activity) with two compounds.Hence, the compounds are useful in calming or sedating warm-bloodedanimals, such as mice, rats, etc. at doses between about 12.7 to 40mg/kg body weight.

The in vivo anti-reserpine activity data was obtained, following theprocedure of Rubin et al., J. Pharm. and Exper. Therap. 120: 1 25, 1957,by administering each of the 1,4-benzodiazepine compounds, at l andmg/kg body weight dose levels to groups of six mice (3 males and 3females). One hour later the animals were challenged with reserpine, 2.5mg/kg body weight, intraperitoneally. The degree of ptosis for eacheye-lid was determined 1 hour after administration of reserpine. Controlgroups of animals are simultaneously run. The results obtained for the1,4-benzodiazepines of Examples 2, 5, and 7, infra, were, expressed asthe ED needed to statistically reverse reserpine induced ptosis of theeyelid in milligrams per kilogram host body weight, 2.8, 15.5, and 1.9,respectively.

EXAMPLE 1 2,3,- 6,7-Tetrahydro-3,3-dimethyl6-phenyl-5l-limidazo[1,2-d][1,4]benzodiazepin-5-one 2-(o-aminophenyl)-5,5-(or 4,4-)-dimethyl-2- imidazoline'(6.00 grams) in methylene chloride(140 milliliters) was added dropwise over a k hour period to a methylenechloride solution containing a-chlorophenylacetyl chloride (5.68 grams)with vigorous stirring. After stirring for an additional hour, thesolution was washed with dilute aqueous hydrochloric acid, neutralizedwith aqueous sodium carbonate and extracted with methylene chloride. Thesolvent was stripped, the residue dissolved in methanol (150milliliters) and the solution treated with triethylamine (10milliliters). After standing for 3 days, the solvents were stripped andthe title compound recovered as its hydrochloride salt (6.73 grams;melting range 243247C.) contaminated with triethylamine hydrochloride.The product was converted to the free base by treatment with aqueoussodium bicarbonate, the triethylamine was removed and the purified freebase was converted to the hydrochloride salt by treatment withisopropanolic HCl to afford 2.66 grams of product with a melting rangeabove 360C.

Following the procedure of the preceding paragraph while employing onehalf the quantities of reactants and allowing the reaction mixture tostand overnight, the seven membered ring was found to have spontaneouslyclosed to afford the title compound as its hydrochloride salt.Recrystallization from alcohol gave 0.925 grams with a melting rangeover 320C.

Elemental analysis for C H ON CI Calcd: C, 66.66; H, 5.84; N, 12.28.Found: C, 66.60; H, 6.01; N, 12.21.

The mass spectral and infra-red data support the structure of theproduct.

EXAMPLE 2 2,5,6,7-Tetrahydro-3,3-dimethyl-6-phenyl-3H-imidazo[1,2-d][1,4]benzodiazepine.

The product of Example 1 (2.64 grams) was converted to the free basewith aqueous sodium bicarbonate, isolated and refluxed with lithiumaluminum hydride (0.350 gram) in tetrahydrofuran milliliters) for 3hours. The crude reduced product was isolated to afford 1.250 grams,melting range 178l C. The hydrochloric acid addition salt was producedas in Example 1 and the product was recrystallized frommethanol-isopropanol to give 1.125 grams, melting range greater than320C.

Elemental analysis for C H N CI Calcd: C, 69.56; H, 6.76; N, 12.81.Found: C, 69.25; H, 6.77; N, 12.62.

The spectral data'displayed no remains of the original carbonyl group.

EXAMPLE 3 2,3 ,6,7-Tetrahydro-6-phenyl-5 H-imidazo 1 ,2-d][ 1,4]benzodiazepin-S-one.

2-(o-A'minophenyl)-2-imidazoline (3.22 grams) in methylene chloridemilliliters) was added to achlorophenylacetyl chloride (3.78 grams) inmethylene chloride (200 milliliters) dropwise and the suspension wasallowed to stand overnight. Filtration of the suspension afforded 4.92grams, melting range 168-172C. with solidification and remelting at215220C. (decomp.) of the hydrochloride of the in- 5. termediate openamide. Allowing 3.7 grams oftthe intermediate. open amide hydrochlorideto stand with triethylam ine 10 milliliters) in methanol (40milliliters) for 3 days provided the title compound as its hydrochloridesalt contaminated with triethylamine ii dro-,

chloride. The free base was formed by treatment'with sodium bicarbonatefollowed by azeotropic removal of the triethylamine, formation of thehydrochloride addi- 7 tion salt and recrystallization from isopropanolgave 2.35 grams of product presenting a melting range over Elementalanalysis for c,,H,,0N,c1. Calcd: C,

65.06; H, 5.14; N, 13.42. Found: C, 65.72; H, 5.26; N,

The spectral data, both infra-red and nuclear magnetic resonance wasconsistent with the structure of the title compound. I

EXAMPLE 4 9-Chloro-2,3,6,7-tetrahydro-6-phenyl-5H-imidazo [1,2-d][1,4]benzodiazepin-5-one. I

2-(o-amino-p chlorophenyl)-2-imidazoline grams) in methylene chloride(70 milliliters) was added to a-chlorophenylacetyl chloride (2.84 grams)in methylene chloride (100 milliliters) dropwise over 1% hour to providethe substituted crude open amide (4.15

Elemental .An'alysis. for C. -,H,' ON- Cl. Calcd: C, 6 ....43. H. 4.52;131 71. .l I

The procedureiof the preceding paragraphzw'as repeated to give"? thesame product, in-somewhat-purer 196-198C EXAMPLE 7 l0- 'Chloro-2,5 ,6,7-tetrahyd ro-6-phenyl-3 H-imidazo [1,2-d][1,4]benzodiazepine.

form, melting range A portion of the product of Example 6 (5.40 grams)was subjected to reduction with LiAlH4 (0.800 grams) in tetrahydrofuran(200 milliliters) under reflux for 4-5 grams; melting range 284287C.).Treatment with triethylamine (10 milliliters) in methanol (70milliliters) for 3 days followed by routine workup provided the titlecompound in crude form. Dry-column chromatography on neutral aluminausing methylene chloride followed by isolation of the product bandprovided, after treatment with isopropanolic HCI, the hydrochlorideaddition salt (1.73 grams; melting range 324-3'26C.). Mass and infra-redspectral analysis confirmed the identity of the product.

EXAMPLE 5 9-Chloro-2,5 ,6,7-tetrahydro-6-phenyl-3H- imidazo[1,2-d][1,4]benzbdiazepine The product of Example 4 was treated with lithiumaluminum hydride in tetrahydrofuran under conditions presented inExample 2 to afford the title compound,

melting range 220-223C.

Elemental analysis for C H N Cl. Calculated; C,

68.51; H, 5.41; N, 14.10. Found: C, 68.13; H, 5.44; N, '1

14.14. Chemical ionization m 1 298.

EXAMPLE 6 l0-Chloro-2,3,6,7-tetrahydro-6-phenyh5H-imidazol,2-d][1,4]benzodiazepin-5-one2-(2-amino-Schlorophenyl)-2-imidazoline (5.5 grams) in methylenechloride (150 milliliters) was added dropwise to a-chlorophenylacetylchloride (6.426 grams) in methylene chloride (300 milliliters). Theintermediate open amide was recovered in an amount of 7.85 grams;melting range l90195C. (sinter), 283285C. (decomp.). Treatment of theopen amide with triethylamine (l5 milliliters in methanol (150milliliters) for a 3 day period followed by evaporation to dryness andpartition between aqueous NaH- CO and methylene chloride and evaporationof liquid provided the title compound (5.40 grams; melting range17s-1s2c.

pharmaceutically acceptable hours. The title compound was isolated andconverted to its hydrochloric acid salt with isopropanolic HCl to afford2.02 grams of the salt, melting range 298300C. Recrystallization fromisopropanolmethanol gave 1.50 grams, melting range 308-3 10C.

Elemental analysis for C,-,H N -,Cl Calcd: C, 61.13; H, 5.13; N, 12.58.Found: C, 60.91; H, 5.11; N, 12.59.

The mass and infra-red spectral data confirmed the structure of thetitle compound.

What is claimed is:

1. A compound of the formula:

in which R is --1-1 or 'c1;

R is H or CH:,; and

acid addition salts thereof.

2. The compound of claim 1 which is 2,3,6,7-tetrahy- N, 13,46. Found: C,64.90; H, 4.73; N,-

pine and pharmaceutically acceptable acid addition The compound f claim1 which is 1() ch|oro Saks thereof I 2,5,6,7-tetrahydro-6-phenyl-3Himidazo benzodiaze- 7. The compound of claim 1 which is lO-chloro-2,3,674etrahydm imidazo benzodiaze pme and pharmaceutically acceptableacid addition 5 salts thereof.

pin-S-one and pharmaceutically acceptable acid addition salts thereof.

1. A COMPOUND OF THE FORMULA-:
 2. The compound of claim 1 which is2,3,6,7-tetrahydro-3,3-dimethyl-6-phenyl-5H-imidazo benzodiazepin-5-oneand pharmaceutically acceptable acid addition salts thereof.
 3. Thecompound of claim 1 which is 2,5,6,7-tetrahydro-3,3-dimethyl-6-phenyl-3H-imidazo benzodaizepine and phrarmaceutically acceptable acid additionsalts thereof.
 4. The compound of claim 1 which is2,3,6,7-tetrahydro-6-phenyl-5H-imidazo benzodiazepin-5-one and thepharmaceutically acceptable acid addition salts thereof.
 5. The compoundof claim 1 which is 9-chloro-2,3,6,7-tetrahydro-6-phenyl-5H-imidazobenzodiazepin-5-one and pharmaceutically acceptable acid addition saltsthereof.
 6. The compound of claim 1 which is 9-chloro-2,5,6,7-tetrahydro6-phenyl-3H-imidazo benzodiazepine and pharmaceutically acceptable acidaddition salts thereof.
 7. The compound of claim 1 which is10-chloro-2,3,6,7-tetrahydro -6-phenyl-5H -imidazo benzodiazepin-5-oneand pharmaceutically acceptable acid addition salts thereof.
 8. Thecompound of claim 1 which is 10-chloro-2,5,6,7-tetrahydro-6-phenyl-3Himidazo benzodiazepine and pharmaceutically acceptable acid additionsalts thereof.